The compound (R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine (also herein referred to as “compound 1”) represented by the formula 1
is a potent small-molecule inhibitor of c-Met/HGFR (hepatocyte growth factor receptor) kinase and ALK (anaplastic lymphoma kinase) activity. Compound 1 has anti-tumor properties that are pharmacologically mediated through inhibition of c-Met/HGFR which is involved in the regulation of growth and metastatic progression of a wide variety of tumors types, and ALK which implicated in the pathogenesis of ALCL (anaplastic large cell lymphoma). Compound 1 is disclosed in International Patent Application No. PCT/IB2005/002837 and U.S. patent application Ser. No. 11/212,331, both of which are herein incorporated by reference in their entirety. Additionally, the racemate of compound 1 is disclosed in International Patent Application No. PCT/IB05/002695 and U.S. patent application Ser. No. 11/213,039, both of which are herein incorporated by reference in their entirety.
Human cancers comprise a diverse array of diseases that collectively are one of the leading causes of death in developed countries throughout the world (American Cancer Society, Cancer Facts and Figures 2005. Atlanta: American Cancer Society; 2005). The progression of cancers is caused by a complex series of multiple genetic and molecular events including gene mutations, chromosomal translocations, and karyotypic abnormalities (Hanahan D, Weinberg R A. The hallmarks of cancer. Cell 2000; 100: 57-70). Although the underlying genetic causes of cancer are both diverse and complex, each cancer type has been observed to exhibit common traits and acquired capabilities that facilitate its progression. These acquired capabilities include dysregulated cell growth, sustained ability to recruit blood vessels (i.e., angiogenesis), and ability of tumor cells to spread locally as well as metastasize to secondary organ sites (Hanahan D, Weinberg R A. The hallmarks of cancer. Cell 2000; 100: 57-70). Therefore, the ability to identify novel therapeutic agents that 1) inhibit molecular targets that are altered during cancer progression or 2) target multiple processes that are common to cancer progression in a variety of tumors presents a significant unmet need.
Example 19 of U.S. patent application Ser. No. 11/212,331 describes the preparation of compound 1 which was found to be amorphous. It is advantageous to have polymorphic forms having improved properties, such as improved crystallinity, dissolution properties, and/or decreased hygroscopicity, while maintaining chemical and enantiomeric stability properties.